Inflammation is a clinically significant medical dysfunction in numerous topical and systemic diseases and its suppression provides a major therapeutic benefit in the treatment of those conditions. Such conditions include, but are not limited to, chemical insults, autoimmune disease, vasculitis, rheumatoid arthritis, atherosclerosis, asthma, hay fever, acne vulgaris, reperfusion injury, dermal abrasions, psoriasis, burns, blisters, inflammatory bowel disease, Alzheimer's dementia, Parkinson's, and other neurodegenerative disorders.
A pharmacologically-attractive binding target, which has been linked closely to modulation of pain and inflammatory responses, is the transient receptor potential vanilloid (TRPV1) also known as the VR1 or the vanilloid/capsaicin receptor. The latter names derive from the fact that TRPV1 binds both the heat sensation-producing component of pepper (capsaicin) as well as a family of fatty amides carrying the 4-hydroxy-3-methoxybenzylamine (vanilloid) moiety. TRPV1 is a non-selective cation channel gated by extracellular protons, heat, and small molecule amides, thioamides, and ureas containing the 4-hydroxy-3-methoxy-benzyl fragment or a prodrug form of the same entity. This 4-hydroxy-3-methoxybenzyl component, as found in the endogenous ligand capsaicin, when attached to a lipophilic moiety virtually guarantees an association with the TRPV1 channel. In human skin, the dermis and the epidermis are rich with TRPV1 positive cells and in patients who have experienced painful inflammation, there is often a marked up-regulation of this receptor.
Medicinal chemists have manipulated the classic vanilloid fatty amide, capsaicin-like platform (Formula (I), wherein Ar=4-hydroxy-3-methoxyphenyl and R=a lipophilic alkyl or cycloalkyl hydrocarbon construct) in search of medically useful drug candidates, by reversing the orientation of the amide functionality. The thus-derived candidate class (Formula (II), wherein Ar=4-hydroxy-3-methoxyphenyl and R=a lipophilic alkyl or cycloalkyl hydrocarbon construct) has been termed the “retro” isomer.Ar—CH2—NH—CO—R  Formula (I)Ar—CH2—CO—NH—R  Formula (II)
Yet another manipulation has been to strategically insert an oxygen atom, thereby converting the traditional fatty acid vanilloid amides into carbamates. In this fashion, analogs of according to Formula (III) and Formula (IV) emerge, both of which possess anti-inflammatory activity.Ar—CH2—NH—CO—O—R  Formula (III)Ar—CH2—O—CO—NH—R  Formula (IV)
Besides TRPV1 as a pharmacological target of merit in pain and inflammation, a case has been made for targeting the matrix metalloproteinases (MMPs), especially MMP-9. MMP-9 has been especially cited as up-regulated in various clinical inflammatory states, and compounds which inhibit MMP-9 display therapeutic potential. The well-known MMP-9 inhibitor, doxycycline, has been shown to be effective in suppressing MMP-9 activated by mustards in vesicant-exposed corneas.
While a variety of molecular architectures have been reported for successful MMP-9 inhibitors, virtually all are chelating agents capable of binding ionic zinc and iron, and among the chelator options the most common construct of all has been the hydroxamic acid (hydroxamate) functionality, viz., —CO—N(OH). The present invention discloses new inhibitors of MMP-9, where the molecular design criteria comprise the inclusion of a hydroxamic functionality proximal to both a lipophilic zone and a substituted phenyl ring.